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Cell Host & Microbe Oct 2023Fungal infections are a global threat; yet, there are no licensed vaccines to any fungal pathogens. Th17 cells mediate immunity to Candida albicans, particularly...
Fungal infections are a global threat; yet, there are no licensed vaccines to any fungal pathogens. Th17 cells mediate immunity to Candida albicans, particularly oropharyngeal candidiasis (OPC), but essential downstream mechanisms remain unclear. In the murine model of OPC, IκBζ (Nfkbiz, a non-canonical NF-κB transcription factor) was upregulated in an interleukin (IL)-17-dependent manner and was essential to prevent candidiasis. Deletion of Nfkbiz rendered mice highly susceptible to OPC. IκBζ was dispensable in hematopoietic cells and acted partially in the suprabasal oral epithelium to control OPC. One prominent IκBζ-dependent gene target was β-defensin 3 (BD3) (Defb3), an essential antimicrobial peptide. Human oral epithelial cells required IκBζ for IL-17-mediated induction of BD2 (DEFB4A, human ortholog of mouse Defb3) through binding to the DEFB4A promoter. Unexpectedly, IκBζ regulated the transcription factor Egr3, which was essential for C. albicans induction of BD2/DEFB4A. Accordingly, IκBζ and Egr3 comprise an antifungal signaling hub mediating mucosal defense against oral candidiasis.
Topics: Humans; Mice; Animals; Candidiasis, Oral; Candida albicans; Candidiasis; Mucous Membrane; Transcription Factors; Adaptor Proteins, Signal Transducing
PubMed: 37725983
DOI: 10.1016/j.chom.2023.08.016 -
PLoS Pathogens Jun 2024Mammalian α-defensins are a family of abundant effector peptides of the mucosal innate immune system. Although primarily considered to be antimicrobial, α-defensins...
Mammalian α-defensins are a family of abundant effector peptides of the mucosal innate immune system. Although primarily considered to be antimicrobial, α-defensins can increase rather than block infection by certain prominent bacterial and viral pathogens in cell culture and in vivo. We have shown previously that exposure of mouse and human adenoviruses (HAdVs) to α-defensins is able to overcome competitive inhibitors that block cell binding, leading us to hypothesize a defensin-mediated binding mechanism that is independent of known viral receptors. To test this hypothesis, we used genetic approaches to demonstrate that none of several primary receptors nor integrin co-receptors are needed for human α-defensin-mediated binding of HAdV to cells; however, infection remains integrin dependent. Thus, our studies have revealed a novel pathway for HAdV binding to cells that bypasses viral primary receptors. We speculate that this pathway functions in parallel with receptor-mediated entry and contributes to α-defensin-enhanced infection of susceptible cells. Remarkably, we also found that in the presence of α-defensins, HAdV tropism is expanded to non-susceptible cells, even when viruses are exposed to a mixture of both susceptible and non-susceptible cells. Therefore, we propose that in the presence of sufficient concentrations of α-defensins, such as in the lung or gut, integrin expression rather than primary receptor expression will dictate HAdV tropism in vivo. In summary, α-defensins may contribute to tissue tropism not only through the neutralization of susceptible viruses but also by allowing certain defensin-resistant viruses to bind to cells independently of previously described mechanisms.
PubMed: 38900833
DOI: 10.1371/journal.ppat.1012317 -
Rheumatology (Oxford, England) Jul 2023To investigate the expression of type I IFN (IFN-I) and neutrophil transcripts in kidney tissue from patients with different classes of LN and their association with...
OBJECTIVES
To investigate the expression of type I IFN (IFN-I) and neutrophil transcripts in kidney tissue from patients with different classes of LN and their association with distinct clinical and histopathological features.
METHODS
Quantitation of IFN-I, defensin-α3 and formyl peptide receptor-like 1 (FPRL-1) transcripts was performed in kidney biopsy tissue from 24 patients with various classes of LN (6 class III, 14 class IV, 4 class V) and 3 control samples. Patient demographics, glomerular filtration rate (eGFR) and histopathological characteristics, including activity and chronicity indices, were analysed.
RESULTS
IFNα2 and IFNβ transcripts were overexpressed in renal tissues from patients with proliferative forms of LN (III/IV) compared with patients with membranous nephritis and control kidneys. Patients with LN and impaired renal function, attested by eGFR, displayed higher relative expression of IFNα2 transcripts in renal tissues compared with those with normal renal function (23.0 ± 16.2 vs 12.0 ± 14.8, P = 0.04). Defensin-α3, but not FPRL-1, transcripts were overexpressed in LN tissues, particularly those with segmental necrotizing lesions, and were correlated with higher renal pathological activity indices (r = 0.61, P = 0.02), urinary protein levels (r = 0.44, P = 0.048) and IFNα2 expression (r = 0.50, P = 0.01).
CONCLUSION
IFN-I transcripts are expressed locally in kidneys from patients with proliferative LN and are associated with impaired renal function. Elevated defensin-α3 transcripts, a neutrophil product associated with neutrophil extracellular traps, may identify a driver of local IFN-I expression. These findings provide insights into the mechanisms of proliferative LN and may inform therapeutic decisions regarding selection of IFN-I pathway inhibitors.
Topics: Humans; Lupus Nephritis; Neutrophils; Kidney; Biopsy; Defensins
PubMed: 36355567
DOI: 10.1093/rheumatology/keac641 -
Current Biology : CB Aug 2023Antibiotic resistance often confers a fitness cost to the resistant cell and thus raises key questions of how resistance is maintained in the absence of antibiotics and,...
Antibiotic resistance often confers a fitness cost to the resistant cell and thus raises key questions of how resistance is maintained in the absence of antibiotics and, if lost, whether cells are genetically primed for re-evolving resistance. To address these questions, we have examined vancomycin-intermediate Staphylococcus aureus (VISA) strains that arise during vancomycin therapy. VISA strains harbor a broad spectrum of mutations, and they are known to be unstable both in patients and in the laboratory. Here, we show that loss of resistance in VISA strains is correlated with a fitness increase and is attributed to adaptive mutations, leaving the initial VISA-adaptive mutations intact. Importantly, upon a second exposure to vancomycin, such revertants evolve significantly faster to become VISA, and they reach higher resistance levels than vancomycin-naive cells. Further, we find that sub-lethal concentrations of vancomycin stabilize the VISA phenotype, as do the human β-defensin 3 (hBD-3) and the bacteriocin nisin that both, like vancomycin, bind to the peptidoglycan building block, lipid II. Thus, factors binding lipid II may stabilize VISA both in vivo and in vitro, and in case resistance is lost, mutations remain that predispose to resistance development. These findings may explain why VISA infections often are re-occurring and suggest that previous vancomycin adaptation should be considered a risk factor when deciding on antimicrobial chemotherapy.
Topics: Humans; Staphylococcus aureus; Vancomycin; Vancomycin Resistance; Anti-Bacterial Agents; Staphylococcal Infections
PubMed: 37494936
DOI: 10.1016/j.cub.2023.06.082 -
International Journal of Molecular... Aug 2023Intestinal diseases caused by protistan parasites of the genera (giardiasis), (amoebiasis), (cryptosporidiosis) and (blastocystosis) represent a major burden in... (Review)
Review
Intestinal diseases caused by protistan parasites of the genera (giardiasis), (amoebiasis), (cryptosporidiosis) and (blastocystosis) represent a major burden in human and animal populations worldwide due to the severity of diarrhea and/or inflammation in susceptible hosts. These pathogens interact with epithelial cells, promoting increased paracellular permeability and enterocyte cell death (mainly apoptosis), which precede physiological and immunological disorders. Some cell-surface-anchored and molecules secreted from these parasites function as virulence markers, of which peptide hydrolases, particularly cysteine proteases (CPs), are abundant and have versatile lytic activities. Upon secretion, CPs can affect host tissues and immune responses beyond the site of parasite colonization, thereby increasing the pathogens' virulence. The four intestinal protists considered here are known to secrete predominantly clan A (C1- and C2-type) CPs, some of which have been characterized. CPs of (e.g., Giardipain-1) and (EhCPs 1-6 and EhCP112) degrade mucin and villin, cause damage to intercellular junction proteins, induce apoptosis in epithelial cells and degrade immunoglobulins, cytokines and defensins. In , five Cryptopains are encoded in its genome, but only Cryptopains 4 and 5 are likely secreted. In sp., a legumain-activated CP, called Blastopain-1, and legumain itself have been detected in the extracellular medium, and the former has similar adverse effects on epithelial integrity and enterocyte survival. Due to their different functions, these enzymes could represent novel drug targets. Indeed, some promising results with CP inhibitors, such as vinyl sulfones (K11777 and WRR605), the garlic derivative, allicin, and purified amoebic CPs have been obtained in experimental models, suggesting that these enzymes might be useful drug targets.
Topics: Animals; Humans; Virulence; Virulence Factors; Cysteine Proteases; Cryptosporidiosis; Cryptosporidium
PubMed: 37629029
DOI: 10.3390/ijms241612850 -
Proceedings of the National Academy of... Nov 2023To mediate critical host-microbe interactions in the human small intestine, Paneth cells constitutively produce abundant levels of α-defensins and other antimicrobials....
To mediate critical host-microbe interactions in the human small intestine, Paneth cells constitutively produce abundant levels of α-defensins and other antimicrobials. We report that the expression profile of these antimicrobials is dramatically askew in human small intestinal organoids (enteroids) as compared to that in paired tissue from which they are derived, with a reduction of α-defensins to nearly undetectable levels. Murine enteroids, however, recapitulate the expression profile of Paneth cell α-defensins seen in tissue. WNT/TCF signaling has been found to be instrumental in the regulation of α-defensins, yet in human enteroids exogenous stimulation of WNT signaling appears insufficient to rescue α-defensin expression. By stark contrast, forkhead box O (FOXO) inhibitor AS1842856 induced the expression of α-defensin mRNA in enteroids by >100,000-fold, restoring and to levels comparable to those found in primary human tissue. These results newly identify FOXO signaling as a pathway of biological and potentially therapeutic relevance for the regulation of human Paneth cell α-defensins in health and disease.
Topics: Humans; Animals; Mice; alpha-Defensins; Intestines; Intestine, Small; Paneth Cells; Anti-Infective Agents; Organoids
PubMed: 37956278
DOI: 10.1073/pnas.2312453120 -
Respiratory Research Nov 2023Severe asthma affects a small proportion of asthmatics but represents a significant healthcare challenge. Bronchial thermoplasty (BT) is an interventional treatment...
RATIONALE
Severe asthma affects a small proportion of asthmatics but represents a significant healthcare challenge. Bronchial thermoplasty (BT) is an interventional treatment approach preconized for uncontrolled severe asthma after considering biologics therapy. It was showed that BT long-lastingly improves asthma control. These improvements seem to be related to the ability of BT to reduce airway smooth muscle remodeling, reduce the number of nerve fibers and to modulate bronchial epithelium integrity and behavior. Current evidence suggest that BT downregulates epithelial mucins expression, cytokine production and metabolic profile. Despite these observations, biological mechanisms explaining asthma control improvement post-BT are still not well understood.
OBJECTIVES
To assess whether BT affects gene signatures in bronchial epithelial cells (BECs).
METHODS
In this study we evaluated the transcriptome of cultured bronchial epithelial cells (BECs) of severe asthmatics obtained pre- and post-BT treatment using microarrays. We further validated gene and protein expressions in BECs and in bronchial biopsies with immunohistochemistry pre- and post-BT treatment.
MEASUREMENTS AND MAIN RESULTS
Transcriptomics analysis revealed that a large portion of differentially expressed genes (DEG) was involved in anti-viral response, anti-microbial response and pathogen induced cytokine storm signaling pathway. S100A gene family stood out as five members of this family where consistently downregulated post-BT. Further validation revealed that S100A7, S100A8, S100A9 and their receptor (RAGE, TLR4, CD36) expressions were highly enriched in severe asthmatic BECs. Further, these S100A family members were downregulated at the gene and protein levels in BECs and in bronchial biopsies of severe asthmatics post-BT. TLR4 and CD36 protein expression were also reduced in BECs post-BT. Thymic stromal lymphopoietin (TSLP) and human β-defensin 2 (hBD2) were significantly decreased while no significant change was observed in IL-25 and IL-33.
CONCLUSIONS
These data suggest that BT might improve asthma control by downregulating epithelial derived S100A family expression and related downstream signaling pathways.
Topics: Humans; Thymic Stromal Lymphopoietin; Bronchial Thermoplasty; Alarmins; Toll-Like Receptor 4; Asthma; Cytokines
PubMed: 37996952
DOI: 10.1186/s12931-023-02604-1 -
Developmental and Comparative Immunology Oct 2023We report differences in the course of infection of G. mellonella larvae with P. entomophila via intrahemocelic and oral routes. Survival curves, larval morphology,...
We report differences in the course of infection of G. mellonella larvae with P. entomophila via intrahemocelic and oral routes. Survival curves, larval morphology, histology, and induction of defence response were investigated. Larvae injected with 10 and 50 cells of P. entomophila activated a dose-dependent immune response, which was manifested by induction of immune-related genes and dose-dependent defence activity in larval hemolymph. In contrast, after the oral application of the pathogen, antimicrobial activity was detected in whole hemolymph of larvae infected with the 10 but not 10 dose in spite of the induction of immune response manifested as immune-relevant gene expression and defence activity of electrophoretically separated low-molecular hemolymph components. Among known proteins induced after the P. entomophila infection, we identified proline-rich peptide 1 and 2, cecropin D-like peptide, galiomycin, lysozyme, anionic peptide 1, defensin-like peptide, and a 27 kDa hemolymph protein. The expression of the lysozyme gene and the amount of protein in the hemolymph were correlated with inactivity of hemolymph in insects orally infected with a higher dose of P. entomophila, pointing to its role in the host-pathogen interaction.
Topics: Animals; Larva; Muramidase; Moths; Peptides; Insecta; Proteins; Hemolymph
PubMed: 37279831
DOI: 10.1016/j.dci.2023.104749 -
Medicina (Kaunas, Lithuania) Jul 2023: Chronic rhinosinusitis with nasal polyps (CRSwNP) presently remains a difficult disease to manage. Antimicrobial and defense proteins are important factors that could...
: Chronic rhinosinusitis with nasal polyps (CRSwNP) presently remains a difficult disease to manage. Antimicrobial and defense proteins are important factors that could help characterize the role of microorganisms in CRSwNP pathogenesis, as the concept of microbial dysbiosis in CRS is still being considered. Our aim is to investigate the complex appearance, relative distribution and interlinks of human β defensin 2 (HBD-2), human β defensin 3 (HBD-3), human β defensin 4 (HBD-4), and cathelicidin LL 37 (LL 37) in chronic rhinosinusitis with nasal polyps (CRSwNP)-affected human nasal mucosa. : The study group consisted of 48 samples from patients with CRSwNP. Samples were collected during functional endoscopic sinus surgery. The control group consisted of 17 normal healthy nasal mucosa samples gathered during routine septoplasty. β-defensin-2, β-defensin-3, β-defensin-4 and cathelicidin LL 37 in tissue were detected via immunohistochemical analysis. : HBD-2, HBD-3 and LL 37 were significantly decreased in epithelial cells in both primary and recurrent nasal polyp samples ( < 0.001) in comparison to control samples. HBD-2 was decreased in the subepithelial connective tissue of primary nasal polyp samples when compared to both recurrent polyp ( = 0.050) and control ( = 0.033) samples. In subepithelial connective tissue, significantly more HBD-3-positive structures were observed in primary nasal polyp samples ( = 0.049) than in control samples. In primary polyp samples, moderate correlations between connective tissue HBD-3 and connective (R = 0.584, = 0.001) and epithelial tissue LL 37 (R = 0.556, = 0.002) were observed. : Decreased HBD-2, HBD-3 and LL 37 concentrations in the epithelium suggest a dysfunction of the epithelial barrier in patients with nasal polyps. Decreased subepithelial connective tissue HBD-2 suggests different responses to nasal microbiota in patients with primary nasal polyps compared to recurrent nasal polyps. Increased HBD-3 in subepithelial connective tissue suggests a possible role of this antimicrobial peptide in the pathogenesis of primary nasal polyps.
Topics: Humans; beta-Defensins; Nasal Polyps; Cathelicidins; Sinusitis; Anti-Infective Agents; Chronic Disease
PubMed: 37512070
DOI: 10.3390/medicina59071259 -
International Journal of Molecular... Jan 2024Psoriasis and atopic dermatitis fall within the category of cutaneous immune-mediated inflammatory diseases (IMIDs). The prevalence of IMIDs is increasing in... (Review)
Review
Psoriasis and atopic dermatitis fall within the category of cutaneous immune-mediated inflammatory diseases (IMIDs). The prevalence of IMIDs is increasing in industrialized societies, influenced by both environmental changes and a genetic predisposition. However, the exact immune factors driving these chronic, progressive diseases are not fully understood. By using multi-omics techniques in cutaneous IMIDs, it is expected to advance the understanding of skin biology, uncover the underlying mechanisms of skin conditions, and potentially devise precise and personalized approaches to diagnosis and treatment. We provide a narrative review of the current knowledge in genomics, epigenomics, and proteomics of atopic dermatitis and psoriasis. A literature search was performed for articles published until 30 November 2023. Although there is still much to uncover, recent evidence has already provided valuable insights, such as proteomic profiles that permit differentiating psoriasis from mycosis fungoides and β-defensin 2 correlation to PASI and its drop due to secukinumab first injection, among others.
Topics: Humans; Dermatitis, Atopic; Multiomics; Proteomics; Psoriasis; Skin Neoplasms; Immunomodulating Agents
PubMed: 38256115
DOI: 10.3390/ijms25021042